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EP0765322B1 - Derives d'indole utilises comme promedicaments contenant des agonistes de recepteurs apparentes au 5-ht-1 - Google Patents

Derives d'indole utilises comme promedicaments contenant des agonistes de recepteurs apparentes au 5-ht-1 Download PDF

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Publication number
EP0765322B1
EP0765322B1 EP95921004A EP95921004A EP0765322B1 EP 0765322 B1 EP0765322 B1 EP 0765322B1 EP 95921004 A EP95921004 A EP 95921004A EP 95921004 A EP95921004 A EP 95921004A EP 0765322 B1 EP0765322 B1 EP 0765322B1
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EP
European Patent Office
Prior art keywords
formula
compound
alkyl
ethyl
indol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP95921004A
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German (de)
English (en)
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EP0765322A1 (fr
Inventor
Robert John Blade
Yih Sang Pang
David Lawrence Selwood
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AstraZeneca AB
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AstraZeneca AB
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Priority to EP95921004A priority Critical patent/EP0765322B1/fr
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Publication of EP0765322B1 publication Critical patent/EP0765322B1/fr
Priority to GR20010401822T priority patent/GR3036953T3/el
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention is concerned with new chemical compounds, their preparation, pharmaceutical formulations containing them and their use in medicine, particularly the prophylaxis and treatment of migraine.
  • 5-hydroxytryptamine 5-hydroxytryptamine
  • 5-HT 5-hydroxytryptamine
  • European Patent Specification 0313397 describes a class of 5-HT agonists which act selectively at a particular subtype of 5-HT 1 receptor and are effective therapeutic agents for the treatment of clinical conditions in which a selective agonist for this type of receptor is indicated.
  • the receptor in question mediates selective cranial arterial vasoconstriction and inhibition of plasma protein extravasation into the dura mater evoked by activation of the Vth (trigeminal) nerve.
  • the compounds described in the European specification are therefore beneficial in the treatment or prophylaxis of conditions wherein these actions are indicated, for example, migraine, a condition associated with and/or neurogenically-evoked inflammation dilation of the cranial vasculature.
  • the target tissue may be any tissue wherein action is mediated by 5-HT 1 receptors of the type referred to above.
  • EP-A-0486666 discloses a class of compounds having exceptional activity at the 5-HT 1 receptor mentioned above and excellent absorption following oral dosing. These properties render the compounds particularly useful for certain medical applications, notably the prophylaxis and treatment of migraine, cluster headache and headache associated with vascular disorders, hereinafter referred to collectively as "migraine”.
  • W is a group of formula (i) and Z is a group of formula (iv).
  • the present invention provides a compound of the formula (Ia) wherein
  • Preferred compounds of formula (Ia) are those wherein n is 1, X is -O- and Y is oxygen.
  • Compounds wherein R 1 and R 2 are independently selected from hydrogen and methyl are preferred, with compounds wherein R 1 and R 2 are both methyl being particularly preferred.
  • Examples of preferred compounds of the invention include:-
  • Physiologically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent, ie basic, compounds. Such salts must clearly have a physiologically acceptable anion.
  • Suitable physiologically acceptable salts of the compounds of the present invention include those derived from acetic, hydrochloric, hydrobromic, phosphoric, malic, maleic, fumaric, citric, sulphuric, lactic, or tartaric acid.
  • the succinate and chloride salts are particularly preferred for medical purposes. Salts having a non-physiologically acceptable anion are within the scope of the invention as useful intermediates for the preparation of physiologically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.
  • a compound of formula (I) or (Ia) or a physiologically acceptable salt or solvate thereof for use as a therapeutic agent specifically as a "5-HT 1 -like" receptor agonist, for example, as a carotid vasoconstrictor or as an inhibitor of neurogenic inflammation in the prophylaxis and treatment of migraine.
  • a therapeutic agent specifically as a "5-HT 1 -like" receptor agonist, for example, as a carotid vasoconstrictor or as an inhibitor of neurogenic inflammation in the prophylaxis and treatment of migraine.
  • target organs for the present compounds other than the carotid vasculature are within the scope of the present invention.
  • a typical daily dose for the treatment of migraine may be expected to lie in the range 0.01 to 5mg per kilogram body weight.
  • Unit doses may contain from 1 to 100mg of a compound of formula (I), for example, ampoules for injection may contain from 1 to 10mg and orally administrable unit dose formulations such as tablets or capsules may contain from 1 to 100mg. Such unit doses may be administered one or more times a day, separately or in multiples thereof.
  • An intravenous dose may be expected to lie in the range 0.01 to 0.15mg/kg and would typically be administered as an infusion of from 0.0003 to 0.15mg per kilogram per minute.
  • Infusion solutions suitable for this purpose may contain from 0.01 to 10mg/ml.
  • the dose is based on the cation (for salts) or the unsolvated compound.
  • compositions comprising, as active ingredient, at least one compound of formula (I) or (Ia) and/or a pharmacologically acceptable salt or solvate thereof together with at least one pharmaceutical carrier or excipient.
  • These pharmaceutical compositions may be used in the prophylaxis or treatment of clinical conditions for which a "5-HT 1 -like" receptor agonist is indicated, for example, migraine.
  • the carrier must be pharmaceutically acceptable to the recipient and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition.
  • the carrier may be a solid or liquid and is preferably formulated with at least one compound of formula (I) or (Ia) as a unit dose formulation, for example, a tablet which may contain from 0.05 to 95% by weight of the active ingredient. If desired, other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.
  • Possible formulations include those suitable for oral, sublingual, buccal, parenteral (for example, subcutaneous, intramuscular, or intravenous), rectal, topical and intranasal administration.
  • parenteral for example, subcutaneous, intramuscular, or intravenous
  • rectal topical and intranasal administration.
  • topical and intranasal administration are particularly suitable.
  • Formulations suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, or lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or nonaqueous liquids; or as oil-in-water or water-in-oil emulsions.
  • Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically, a flavoured base, such as sugar and acacia or tragacanth, and pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose and acacia.
  • a flavoured base such as sugar and acacia or tragacanth
  • an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution is preferably isotonic with the blood of the intended recipient. Although such solutions are preferably administered intravenously, they may also be administered by subcutaneous or intramuscular injection.
  • Formulations suitable for rectal administration are preferably provided as unit-dose suppositories comprising the active ingredient and one or more solid carriers forming the suppository base, for example, cocoa butter.
  • Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils.
  • Suitable carriers for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof.
  • the active ingredient is typically present in such formulations at a concentration of from 0.1 to 15%w/w.
  • the formulations of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.
  • a tablet may be prepared by compressing an intimate mixture comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
  • one or more optional ingredients such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
  • Aqueous solutions for parenteral administration are typically prepared by dissolving the active compound in sufficient water to give the desired concentration and then rendering the resulting solution sterile and isotonic.
  • a compound of formula (I) or (Ia) in the preparation of a medicament for the prophylaxis or treatment of a clinical condition for which a "5-HT 1 -like" receptor agonist is indicated, for example, migraine.
  • a method for the prophylaxis or treatment of a clinical condition in a mammal for example, a human, for which a "5-HT 1 -like" receptor agonist is indicated, for example, migraine, which comprises the administration to said mammal of a therapeutically effective amount of a compound of formula (I) or (Ia) or of a physiologically acceptable salt or solvate thereof.
  • the present invention also provides, in a seventh aspect, a process for the preparation of a compound of formula (I) or Ia).
  • This process comprises reaction of a compound of formula (II). wherein W, Z and n are as hereinbefore defined, with a compound of formula (III) wherein A is as hereinbefore defined.
  • the reaction is preferably carried out in the presence of a base such as an organic base, for example triethylamine, pyridine or Hunig's base, or an inorganic base, for example sodium hydride or potassium carbonate.
  • a base such as an organic base, for example triethylamine, pyridine or Hunig's base, or an inorganic base, for example sodium hydride or potassium carbonate.
  • Sodium hydride is preferred.
  • the reaction may be carried out in polar aprotic solvents such as dimethylformamide, dimethylsulphoxide or in chlorinated solvents such as dichloromethane. Dimethylformamide is the preferred solvent.
  • the reaction may be carried out in the temperature range 0-100°. 0° to room temperature is preferred.
  • compounds of formula (I) or (Ia) may be prepared by reaction of a compound of formula (II) or (IIa) with a compound of formula (IV) wherein A is as hereinbefore defined.
  • the reaction is preferably carried out in the presence of a base such as an organic base, for example triethylamine, pyridine or dimethylamino pyridine or an inorganic base for example sodium hydride or potassium carbonate.
  • a base such as an organic base, for example triethylamine, pyridine or dimethylamino pyridine or an inorganic base for example sodium hydride or potassium carbonate.
  • Dimethylaminopyridine is preferred when it is desired to make the compound 4-[1-t-Butyloxycarbonyl-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl] oxazolidin-2-one acetate.
  • Sodium hydride is the preferred base when it is desired to make the compound 4-[1-Acetyl-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl]oxazolidin-2-one acetate.
  • the reaction may be carried out in polar aprotic solvents such as acetonitrile, dimethylformamide, dimethylsulphoxide or in chlorinated solvents such as dichloromethane.
  • Acetonitrile is the preferred solvent for synthesis of the compound 4-[1-t-Butyloxycarbonyl-3-[2-(dimethylamino)ethyl]indol-5-yl methyl]oxazolidin-2-one acetate.
  • Dimethylformamide is the preferred solvent for synthesis of the compound 4-[1-Acetyl-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl] oxazolidin-2-one acetate.
  • the reaction may be carried out in the temperature range 0-100°. 0° to room temperature is preferred.
  • Salts and solvates of Compounds of formula (I) or (Ia) may be prepared from compounds of formula (I) or (Ia) using standard techniques known in the art.
  • Example 1 4-[1-Benzoyl-3-[2-(dimethylarnino)ethyl]indol-5-ylmethyl] oxazolidin-2-one acetate
  • the reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic phase was washed with brine and dried over magnesium sulphate.
  • the crude product was purified by (a) chromatography on silica, eluting with dichloromethane/methanol/ammonia (90:10:0.5) and then (b) Reverse phase HPLC on a C 8 column eluting with acetonitrile/water/ammonium acetate to give, after freeze-drying, the title product as a colourless amorphous solid (with 1.0 ACOH).
  • Example 3 4-[1-(2'-toluoyl)-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl] oxazolidin-2-one acetate
  • Example 6 4-[1-Acetyl-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl]oxazolidin-2 -one acetate
  • reaction mixture was partitioned between chloroform and saturated aqueous ammonium chloride.
  • organic phase was dried over magnesium sulphate and the crude product pruified by Reverse Phase HPLC on a C8 column eluting with acetonitrile/water/ammonium acetate. Freeze drying afforded the title compound.
  • the "active ingredient” may be any compound of formula (I) or (Ia) and/or a physiologically acceptable salt, solvate, or physiologically functional derivative thereof.
  • the peak plasma concentration (Cmax) of 4-[1-acetyl-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl]oxazolidin-2-one acetate was approx 0.2 ⁇ g/ml (5 min) and this parent compound was detectable up to 1 h post dose (limit of detection 0.02 ⁇ g/ml); the plasma half-life was approximately 0.2 h.
  • the breakdown product, 4-[3-[2-(dimethylamino)ethyl]-1H-indol-5-ylmethyl]-2-oxazolidinone was also detected in the plasma (Cmax 0.3 ⁇ g/ml, 5 min) up to 4 h after dosing.
  • Example 3 The compound of Example 3 was incubated with rat hepalocytes to determine whether the active compound, 4-[3-[2-(dimethylamino)ethyl]-1H-indol-5-ylmethyl]-2-oxazolidinone, is a main product of its metabolism. After 30 minutes incubation, no compound of Example 3 remained, while approximately 50% had been converted to the active compound.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Claims (10)

  1. Composé de formule (I)
    Figure 00250001
    dans laquelle
    A est alkyle en C1-6, -O-alkyle en C1-6 ou -O-phényle ou phényle, éventuellement substitué par alkyle en C1-3 ou halogène ;
    n est un entier de 0 à 3 ;
    W est un groupement de formule (i), (ii) ou (iii)
    Figure 00250002
    dans laquelle R est hydrogène ou alkyle en C1-4, X est -O-, -S-, -NH-, ou -CH2-, Y est oxygène ou soufre et le centre chiral * dans la formule (i) ou (ii) est sous sa forme (S) ou (R) ou est un mélange de celles-ci dans des proportions quelconques ; et
    Z est un groupement de formule (iv), (v) ou (vi)
    Figure 00260001
    dans laquelle R1 et R2 sont choisis indépendamment parmi hydrogène ou alkyle en C1-4 et R3 est hydrogène ou alkyle en C1-4;
    et les sels et solvates de celui-ci.
  2. Composé de formule (Ia)
    Figure 00260002
    dans laquelle
    A est alkyle en C1-6, -O-alkyle en C1-6 ou -O-phényle ou phényle, éventuellement substitué par alkyle en C1-3 ou halogène ;
    n est un entier de 0 à 3 ;
    R est hydrogène ou alkyle en C1-4;
    X est -O-, -S-, -NH-, ou -CH2- ;
    Y est oxygène ou soufre ; et
    R1 et R2 sont choisis indépendamment parmi hydrogène ou alkyle en C1-4, et les sels et solvates de celui-ci.
  3. Composé selon la revendication 1 ou la revendication 2, caractérisé en ce que R1 et R2 sont tous deux méthyle, et les sels et solvates de celui-ci.
  4. Composé selon la revendication 2 ou la revendication 3, caractérisé en ce que X est -O- et Y est oxygène, et les sels et solvates de celui-ci.
  5. Formulation pharmaceutique comprenant au moins un composé de formule (I) ou de formule (Ia) telles que définies dans la présente, conjointement avec un ou plusieurs supports et/ou excipients pharmaceutiquement acceptables.
  6. Composé de formule (I) ou de formule (Ia) telles que définies dans la présente, destiné à être utilisé en thérapie.
  7. Utilisation d'un composé de formule (I) ou (Ia) tels que définis dans la présente, dans la fabrication d'un médicament destiné à être utilisé dans la prophylaxie ou le traitement de la migraine.
  8. Procédé de préparation d'un composé selon l'une quelconque des revendications 1 à 6, procédé comprenant
    a) la réaction d'un composé de formule (II)
    Figure 00270001
    dans laquelle W, n et Z sont tels que définis dans la revendication 1, avec un composé de formule (III)
    Figure 00270002
    dans laquelle A est tel que défini dans la revendication 1 ou
    b) la réaction d'un composé de formule (II) avec un composé de formule (IV)
    Figure 00280001
    éventuellement suivie de la formulation de sels ou de solvates.
  9. Procédé selon la revendication 8, pour la préparation d'un composé de formule (Ia), procédé comprenant la réaction d'un composé de formule (IIa)
    Figure 00280002
    avec un composé de formule (III) ou de formule (IV).
  10. La 4-[1-benzyloxycarbonyl-3-[2-(diméthylamino)éthyl]indol-5-ylméthyl]oxazolidin-2-one.
EP95921004A 1994-06-01 1995-05-31 Derives d'indole utilises comme promedicaments contenant des agonistes de recepteurs apparentes au 5-ht-1 Expired - Lifetime EP0765322B1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP95921004A EP0765322B1 (fr) 1994-06-01 1995-05-31 Derives d'indole utilises comme promedicaments contenant des agonistes de recepteurs apparentes au 5-ht-1
GR20010401822T GR3036953T3 (en) 1994-06-01 2001-10-19 Indole derivatives as prodrugs of 5-ht 1?-like receptor agonists

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP94303928 1994-01-06
EP94303928 1994-06-01
EP95921004A EP0765322B1 (fr) 1994-06-01 1995-05-31 Derives d'indole utilises comme promedicaments contenant des agonistes de recepteurs apparentes au 5-ht-1
PCT/GB1995/001249 WO1995032966A1 (fr) 1994-06-01 1995-05-31 Derives d'indole utilises comme promedicaments contenant des agonistes de recepteurs apparentes au 5-ht¿1?

Publications (2)

Publication Number Publication Date
EP0765322A1 EP0765322A1 (fr) 1997-04-02
EP0765322B1 true EP0765322B1 (fr) 2001-07-25

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EP95921004A Expired - Lifetime EP0765322B1 (fr) 1994-06-01 1995-05-31 Derives d'indole utilises comme promedicaments contenant des agonistes de recepteurs apparentes au 5-ht-1

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Country Link
US (1) US5962486A (fr)
EP (1) EP0765322B1 (fr)
JP (1) JP3262800B2 (fr)
AT (1) ATE203533T1 (fr)
AU (1) AU2621995A (fr)
DE (1) DE69521895T2 (fr)
DK (1) DK0765322T3 (fr)
ES (1) ES2161892T3 (fr)
GR (1) GR3036953T3 (fr)
PT (1) PT765322E (fr)
WO (1) WO1995032966A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9515305D0 (en) * 1995-07-26 1995-09-20 Wellcome Found Therapeutic heterocyclic compounds
US6909005B1 (en) * 1995-08-07 2005-06-21 Astrazeneca Uk Limited One post synthesis of 2-oxazolidinone derivatives
CA2268399C (fr) * 1996-10-31 2008-08-19 Harbor Branch Oceanographic Institution, Inc. Composes et compositions inflammatoires antineurogenes et methodes d'utilisation
WO1999042092A2 (fr) * 1998-02-20 1999-08-26 Harbor Branch Oceanographic Institution, Inc. Compose et procedes utilises pour traiter une inflammation neurogenique

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8724912D0 (en) * 1987-10-23 1987-11-25 Wellcome Found Indole derivatives
AU646871B2 (en) * 1990-06-07 1994-03-10 Astrazeneca Uk Limited Therapeutic heterocyclic compounds
TW263508B (fr) * 1991-02-12 1995-11-21 Pfizer
GB9208463D0 (en) * 1992-04-16 1992-06-03 Merck Sharp & Dohme Therapeutic agents
FR2701026B1 (fr) * 1993-02-02 1995-03-31 Adir Nouveaux dérivés de l'indole, de l'indazole et du benzisoxazole, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent.

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JP3262800B2 (ja) 2002-03-04
DE69521895T2 (de) 2002-04-04
EP0765322A1 (fr) 1997-04-02
DE69521895D1 (de) 2001-08-30
AU2621995A (en) 1995-12-21
ES2161892T3 (es) 2001-12-16
GR3036953T3 (en) 2002-01-31
US5962486A (en) 1999-10-05
JPH10500987A (ja) 1998-01-27
WO1995032966A1 (fr) 1995-12-07
DK0765322T3 (da) 2001-10-22
ATE203533T1 (de) 2001-08-15
PT765322E (pt) 2002-01-30

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